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Drug Interactions between Di-Phen and Pepcid Complete

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

famotidine phenytoin

Applies to: Pepcid Complete (calcium carbonate / famotidine / magnesium hydroxide) and Di-Phen (phenytoin)

MONITOR: Coadministration with famotidine or ranitidine may rarely increase the plasma concentrations of phenytoin, resulting in toxicity. The mechanism of interaction is unknown. Neither famotidine nor ranitidine has been shown to significantly inhibit CYP450-mediated oxidative metabolism at therapeutic dosages. In addition, no effects on clearance or plasma levels of phenytoin were reported during coadministration with famotidine or ranitidine in separate pharmacokinetic studies. Data suggesting a potential interaction are limited to isolated case reports of phenytoin toxicity shortly after initiation or dosage increase of the H2-receptor antagonist. In at least a couple cases, the patient was elderly and had underlying conditions that may have contributed to the development of toxicity (e.g., renal dysfunction, hypoalbuminemia).

MANAGEMENT: Until more information is available, caution is advised if phenytoin is prescribed in combination with famotidine or ranitidine, particularly in elderly patients. Clinicians should be alert for signs and symptoms of phenytoin toxicity such as ataxia, incoordination, tremor, nystagmus, hypotension, slurred speech, lethargy, nausea, vomiting, mental confusion, and psychosis. The possibility of an interaction should be considered if toxicity occurs shortly (e.g., within a month) after initiation or change of dosage of the H2-receptor antagonist. Both phenytoin and the H2-receptor antagonist may need to be withdrawn until the patient recovers.

References

  1. Richards DA (1983) "Comparative pharmacodynamics and pharmacokinetics of cimetidine and ranitidine." J Clin Gastroenterol, 5, p. 81-90
  2. Karlstadt RG, Palmer RH, Shinn AF (1991) "Unrecognized drug interactions with famotidine and nizatidine." Arch Intern Med, 151, 610, 614-5
  3. Smith SR, Kendall MJ (1988) "Ranitidine versus cimetidine: a comparison of their potential to cause clinically important drug interactions." Clin Pharmacokinet, 15, p. 44-56
  4. Bramhall D, Levine M (1988) "Possible interaction of ranitidine with phenytoin." Drug Intell Clin Pharm, 22, p. 979-80
  5. Humphries TJ (1987) "Famotidine: a notable lack of drug interactions." Scand J Gastroenterol Suppl, 134, p. 55-60
  6. (2002) "Product Information. Pepcid (famotidine)." Merck & Co., Inc
  7. (2001) "Product Information. Zantac (ranitidine)." Glaxo Wellcome
  8. Tse CS, Iagmin P (1994) "Phenytoin and ranitidine interaction." Ann Intern Med, 120, p. 892-3
  9. Powell JR, Donn KH (1984) "Histamine H2-antagonist drug interactions in perspective: mechanistic concepts and clinical implications." Am J Med, 77, p. 57-84
  10. Williams D, Kelly A, Feely J (2000) "Drug interactions avoided - a useful indicator of good prescribing practice." Br J Clin Pharmacol, 49, p. 369-72
  11. Khan AY, Kalimuddin MN, Gorman JM (2007) "Neuropsychiatric manifestations of phenytoin toxicity in an elderly patient." J Psychiatr Pract, 13, p. 49-54
  12. Sambol NC, Upton RA, Chremos AN, Lin ET, Williams RL (1989) "A comparison of the influence of famotidine and cimetidine on phenytoin elimination and hepatic blood flow." Br J Clin Pharmacol, 27, p. 83-7
  13. Watts RW, Hetzel DJ, Bochner F, Hallpike JF, Hann CS, Shearman DJ (1983) "Lack of interaction between ranitidine and phenytoin." Br J Clin Pharmacol, 15, p. 499-500
View all 13 references

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Moderate

phenytoin calcium carbonate

Applies to: Di-Phen (phenytoin) and Pepcid Complete (calcium carbonate / famotidine / magnesium hydroxide)

ADJUST DOSING INTERVAL: Concurrent administration of antacids may decrease the bioavailability of phenytoin. The mechanism of interaction is unknown. In eight healthy volunteers, coadministration of a single 600 mg dose of phenytoin and an antacid containing either aluminum-magnesium hydroxide or calcium carbonate (dose equal to 160 mEq of neutralizing capacity) given one and three hours after meals and at bedtime on the same day resulted in an approximately 25% reduction in the total area under the concentration-time curve (AUC) of phenytoin compared to administration alone. An antacid containing aluminum hydroxide-magnesium trisilicate given in an equivalent dose also reduced the AUC of phenytoin, but the difference was not statistically significant. In another study, aluminum hydroxide-magnesium trisilicate caused a 12% reduction in steady-state serum phenytoin levels in six epileptic patients, but seizure frequency was not affected. There have also been isolated case reports of patients with low serum phenytoin levels or inadequate seizure control attributed to concurrent antacid administration. In a few of the patients, serum phenytoin levels rose two to threefold when antacid administration was delayed by 2 to 3 hours. However, some studies have failed to find a significant interaction with these antacids.

MANAGEMENT: Given the narrow therapeutic index and the large interindividual variability in the pharmacokinetics of phenytoin, patients requiring concomitant antacid therapy should consider separating the times of administration by at least two to three hours if possible. Serum phenytoin levels and seizure activity should be monitored.

References

  1. D'Arcy PF, McElnay JC (1987) "Drug-antacid interactions: assessment of clinical importance." Drug Intell Clin Pharm, 21, p. 607-17
  2. O'Brien LS, Orme ML, Breckenridge AM (1978) "Failure of antacids to alter the pharmacokinetics of phenytoin." Br J Clin Pharmacol, 6, p. 176-7
  3. Kulshrestha K, Thomas M, Wadsworth J, Richens A (1978) "Interaction between phenytoin and antacids." Br J Clin Pharmacol, 6, p. 177-9
  4. Carter BL, Garnett WR, Pellock JM, et al. (1981) "Effects of antacids on phenytoin bioavailability." Ther Drug Monit, 3, p. 333-40
  5. (2001) "Product Information. Dilantin (phenytoin)." Parke-Davis
  6. Kutt H (1975) "Interactions of antiepileptic drugs." Epilepsia, 16, p. 393-402
  7. Chapron DJ, Kramer PA, Mariano SL, Hohnadel DC (1979) "Effect of calcium and antacids on phenytoin bioavailability." Arch Neurol, 36, p. 436-8
View all 7 references

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Moderate

phenytoin magnesium hydroxide

Applies to: Di-Phen (phenytoin) and Pepcid Complete (calcium carbonate / famotidine / magnesium hydroxide)

ADJUST DOSING INTERVAL: Concurrent administration of antacids may decrease the bioavailability of phenytoin. The mechanism of interaction is unknown. In eight healthy volunteers, coadministration of a single 600 mg dose of phenytoin and an antacid containing either aluminum-magnesium hydroxide or calcium carbonate (dose equal to 160 mEq of neutralizing capacity) given one and three hours after meals and at bedtime on the same day resulted in an approximately 25% reduction in the total area under the concentration-time curve (AUC) of phenytoin compared to administration alone. An antacid containing aluminum hydroxide-magnesium trisilicate given in an equivalent dose also reduced the AUC of phenytoin, but the difference was not statistically significant. In another study, aluminum hydroxide-magnesium trisilicate caused a 12% reduction in steady-state serum phenytoin levels in six epileptic patients, but seizure frequency was not affected. There have also been isolated case reports of patients with low serum phenytoin levels or inadequate seizure control attributed to concurrent antacid administration. In a few of the patients, serum phenytoin levels rose two to threefold when antacid administration was delayed by 2 to 3 hours. However, some studies have failed to find a significant interaction with these antacids.

MANAGEMENT: Given the narrow therapeutic index and the large interindividual variability in the pharmacokinetics of phenytoin, patients requiring concomitant antacid therapy should consider separating the times of administration by at least two to three hours if possible. Serum phenytoin levels and seizure activity should be monitored.

References

  1. D'Arcy PF, McElnay JC (1987) "Drug-antacid interactions: assessment of clinical importance." Drug Intell Clin Pharm, 21, p. 607-17
  2. O'Brien LS, Orme ML, Breckenridge AM (1978) "Failure of antacids to alter the pharmacokinetics of phenytoin." Br J Clin Pharmacol, 6, p. 176-7
  3. Kulshrestha K, Thomas M, Wadsworth J, Richens A (1978) "Interaction between phenytoin and antacids." Br J Clin Pharmacol, 6, p. 177-9
  4. Carter BL, Garnett WR, Pellock JM, et al. (1981) "Effects of antacids on phenytoin bioavailability." Ther Drug Monit, 3, p. 333-40
  5. (2001) "Product Information. Dilantin (phenytoin)." Parke-Davis
  6. Kutt H (1975) "Interactions of antiepileptic drugs." Epilepsia, 16, p. 393-402
  7. Chapron DJ, Kramer PA, Mariano SL, Hohnadel DC (1979) "Effect of calcium and antacids on phenytoin bioavailability." Arch Neurol, 36, p. 436-8
View all 7 references

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Minor

famotidine calcium carbonate

Applies to: Pepcid Complete (calcium carbonate / famotidine / magnesium hydroxide) and Pepcid Complete (calcium carbonate / famotidine / magnesium hydroxide)

Antacids and some aluminum, calcium, and magnesium salts may decrease the plasma concentrations of H2-receptor antagonists during oral coadministration. The mechanism of interaction is unknown, but may involve reduced oral absorption due to increased gastric pH. Study data vary, with no changes to nearly 60% reductions in systemic exposures (AUCs) reported for cimetidine, famotidine, and ranitidine. The clinical significance has not been established. As a precaution, patients may consider taking H2-receptor antagonists one to two hours before antacids.

References

  1. Donn KH, Eshelman FN, Plachetka JR, et al. (1984) "The effects of antacid and propantheline on the absorption of oral ranitidine." Pharmacotherapy, 4, p. 89-92
  2. Albin H, Vincon G, Demotes-Mainard F, et al. (1984) "Effect of aluminium phosphate on the bioavailability of cimetidine and prednisolone." Eur J Clin Pharmacol, 26, p. 271-3
  3. Lin JH, Chremos AN, Kanovsky SM, Schwartz S, Yeh KC, Kann J (1987) "Effects of antacids and food on absorption of famotidine." Br J Clin Pharmacol, 24, p. 551-3
  4. Bodemar G, Norlander B, Walan A (1979) "Diminished absorption of cimetidine caused by antacids." Lancet, 02/24/79, p. 444-5
  5. Steinberg WM, Lewis JH, Katz DM (1982) "Antacids inhibit absorption of cimetidine." N Engl J Med, 307, p. 400-4
  6. Barzaghi N, Gatti G, Crema F, Perucca E (1989) "Impaired bioavailability of famotidine given concurrently with a potent antacid." J Clin Pharmacol, 29, p. 670-2
  7. Russell WL, Lopez LM, Normann SA, et al. (1984) "Effect of antacids on predicted steady-state cimetidine concentrations." Dig Dis Sci, 29, p. 385-9
  8. Shelly DW, Doering PL, Russell WL, Guild RT, Lopez LM, Perrin J (1986) "Effect of concomitant antacid administration on plasma cimetidine concentrations during repetitive dosing." Drug Intell Clin Pharm, 20, p. 792-5
  9. Albin H, Vincon G, Begaud B, Bistue C, Perez P (1987) "Effect of aluminum phosphate on the bioavailability of ranitidine." Eur J Clin Pharmacol, 32, p. 97-9
  10. Mihaly GW, Marino AT, Webster LK, Jones DB, Louis WJ, Smallwood RA (1982) "High dose of antacid (Mylanta II) reduces bioavailability of ranitidine." Br Med J, 285, p. 998-9
  11. Covington TR, eds., Lawson LC, Young LL (1993) "Handbook of Nonprescription Drugs." Washington, DC: American Pharmaceutical Association
  12. Bachmann KA, Sullivan TJ, Jauregui L, Reese J, Miller K, Levine L (1994) "Drug interactions of h-2-receptor antagonists." Scand J Gastroenterol, 29, p. 14-9
View all 12 references

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Minor

famotidine magnesium hydroxide

Applies to: Pepcid Complete (calcium carbonate / famotidine / magnesium hydroxide) and Pepcid Complete (calcium carbonate / famotidine / magnesium hydroxide)

Antacids and some aluminum, calcium, and magnesium salts may decrease the plasma concentrations of H2-receptor antagonists during oral coadministration. The mechanism of interaction is unknown, but may involve reduced oral absorption due to increased gastric pH. Study data vary, with no changes to nearly 60% reductions in systemic exposures (AUCs) reported for cimetidine, famotidine, and ranitidine. The clinical significance has not been established. As a precaution, patients may consider taking H2-receptor antagonists one to two hours before antacids.

References

  1. Donn KH, Eshelman FN, Plachetka JR, et al. (1984) "The effects of antacid and propantheline on the absorption of oral ranitidine." Pharmacotherapy, 4, p. 89-92
  2. Albin H, Vincon G, Demotes-Mainard F, et al. (1984) "Effect of aluminium phosphate on the bioavailability of cimetidine and prednisolone." Eur J Clin Pharmacol, 26, p. 271-3
  3. Lin JH, Chremos AN, Kanovsky SM, Schwartz S, Yeh KC, Kann J (1987) "Effects of antacids and food on absorption of famotidine." Br J Clin Pharmacol, 24, p. 551-3
  4. Bodemar G, Norlander B, Walan A (1979) "Diminished absorption of cimetidine caused by antacids." Lancet, 02/24/79, p. 444-5
  5. Steinberg WM, Lewis JH, Katz DM (1982) "Antacids inhibit absorption of cimetidine." N Engl J Med, 307, p. 400-4
  6. Barzaghi N, Gatti G, Crema F, Perucca E (1989) "Impaired bioavailability of famotidine given concurrently with a potent antacid." J Clin Pharmacol, 29, p. 670-2
  7. Russell WL, Lopez LM, Normann SA, et al. (1984) "Effect of antacids on predicted steady-state cimetidine concentrations." Dig Dis Sci, 29, p. 385-9
  8. Shelly DW, Doering PL, Russell WL, Guild RT, Lopez LM, Perrin J (1986) "Effect of concomitant antacid administration on plasma cimetidine concentrations during repetitive dosing." Drug Intell Clin Pharm, 20, p. 792-5
  9. Albin H, Vincon G, Begaud B, Bistue C, Perez P (1987) "Effect of aluminum phosphate on the bioavailability of ranitidine." Eur J Clin Pharmacol, 32, p. 97-9
  10. Mihaly GW, Marino AT, Webster LK, Jones DB, Louis WJ, Smallwood RA (1982) "High dose of antacid (Mylanta II) reduces bioavailability of ranitidine." Br Med J, 285, p. 998-9
  11. Covington TR, eds., Lawson LC, Young LL (1993) "Handbook of Nonprescription Drugs." Washington, DC: American Pharmaceutical Association
  12. Bachmann KA, Sullivan TJ, Jauregui L, Reese J, Miller K, Levine L (1994) "Drug interactions of h-2-receptor antagonists." Scand J Gastroenterol, 29, p. 14-9
View all 12 references

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Drug and food interactions

Moderate

phenytoin food

Applies to: Di-Phen (phenytoin)

ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

References

  1. Sandor P, Sellers EM, Dumbrell M, Khouw V (1981) "Effect of short- and long-term alcohol use on phenytoin kinetics in chronic alcoholics." Clin Pharmacol Ther, 30, p. 390-7
  2. Holtz L, Milton J, Sturek JK (1987) "Compatibility of medications with enteral feedings." JPEN J Parenter Enteral Nutr, 11, p. 183-6
  3. Sellers EM, Holloway MR (1978) "Drug kinetics and alcohol ingestion." Clin Pharmacokinet, 3, p. 440-52
  4. (2001) "Product Information. Dilantin (phenytoin)." Parke-Davis
  5. Doak KK, Haas CE, Dunnigan KJ, et al. (1998) "Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings." Pharmacotherapy, 18, p. 637-45
  6. Rodman DP, Stevenson TL, Ray TR (1995) "Phenytoin malabsorption after jejunostomy tube delivery." Pharmacotherapy, 15, p. 801-5
  7. Au Yeung SC, Ensom MH (2000) "Phenytoin and enteral feedings: does evidence support an interaction?" Ann Pharmacother, 34, p. 896-905
  8. Ozuna J, Friel P (1984) "Effect of enteral tube feeding on serum phenytoin levels." J Neurosurg Nurs, 16, p. 289-91
  9. Faraji B, Yu PP (1998) "Serum phenytoin levels of patients on gastrostomy tube feeding." J Neurosci Nurs, 30, p. 55-9
  10. Marvel ME, Bertino JS (1991) "Comparative effects of an elemental and a complex enteral feeding formulation on the absorption of phenytoin suspension." JPEN J Parenter Enteral Nutr, 15, p. 316-8
  11. Fleisher D, Sheth N, Kou JH (1990) "Phenytoin interaction with enteral feedings administered through nasogastric tubes." JPEN J Parenter Enteral Nutr, 14, p. 513-6
  12. Haley CJ, Nelson J (1989) "Phenytoin-enteral feeding interaction." DICP, 23, p. 796-8
  13. Guidry JR, Eastwood TF, Curry SC (1989) "Phenytoin absorption in volunteers receiving selected enteral feedings." West J Med, 150, p. 659-61
  14. Krueger KA, Garnett WR, Comstock TJ, Fitzsimmons WE, Karnes HT, Pellock JM (1987) "Effect of two administration schedules of an enteral nutrient formula on phenytoin bioavailability." Epilepsia, 28, p. 706-12
  15. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  16. Cerner Multum, Inc. "Australian Product Information."
View all 16 references

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Moderate

calcium carbonate food

Applies to: Pepcid Complete (calcium carbonate / famotidine / magnesium hydroxide)

ADJUST DOSING INTERVAL: Administration with food may increase the absorption of calcium. However, foods high in oxalic acid (spinach or rhubarb), or phytic acid (bran and whole grains) may decrease calcium absorption.

MANAGEMENT: Calcium may be administered with food to increase absorption. Consider withholding calcium administration for at least 2 hours before or after consuming foods high in oxalic acid or phytic acid.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Canadian Pharmacists Association (2006) e-CPS. http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink
  3. Cerner Multum, Inc. "Australian Product Information."
  4. Agencia Española de Medicamentos y Productos Sanitarios Healthcare (2008) Centro de información online de medicamentos de la AEMPS - CIMA. https://cima.aemps.es/cima/publico/home.html
  5. Mangels AR (2014) "Bone nutrients for vegetarians." Am J Clin Nutr, 100, epub
  6. Davies NT (1979) "Anti-nutrient factors affecting mineral utilization." Proc Nutr Soc, 38, p. 121-8
View all 6 references

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Minor

famotidine food

Applies to: Pepcid Complete (calcium carbonate / famotidine / magnesium hydroxide)

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.

References

  1. Bendayan R, Sullivan JT, Shaw C, Frecker RC, Sellers EM (1990) "Effect of cimetidine and ranitidine on the hepatic and renal elimination of nicotine in humans." Eur J Clin Pharmacol, 38, p. 165-9

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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